Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.
Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus that has been implicated as the major causative agent in non-A, non-B hepatitis; an HCV protease necessary for polypeptide processing and viral replication has been identified. U.S. Pat. No. 7,012,066 discloses a genus of HCV protease inhibitor compounds that includes the compound of Formula I, (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]-carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide.

US2005/0059800, published Mar. 17, 2005, discloses a process for preparing the compound of Formula I and discloses a bisulfite adduct of Formula I which can be used to provide the compound in a pure form in accordance with the methods taught in Advanced Organic Chemistry, 4th ed., Jerry March Ed., John Wiley and Sons, 1972.
US2005/0020669, filed Jan. 27, 2005, discloses processes for preparing an intermediate useful in preparing the compound of Formula I. Methods for preparing diastereomers of the compound of Formula I are disclosed in US2005/0249702, filed Nov. 10, 2005. Published US Patent Application No. 2007/0149459, filed Nov. 13, 2006, discloses oxidation processes for preparing the compound of Formula I.
Purification of the compound of Formula I is difficult for several reasons. The compound Formula I is an alpha-keto amide that is unstable and forms dimers, especially under basic conditions. Also, the compound of Formula I is amorphous, thus it does not crystallize and precipitation does not improve the purity of the solid.
Previously published procedures for preparing the compound of Formula I resulted in about 63 to about 98.5% purity.
Historically, aldehydes and ketones have been purified by preparing their bisulfite adduct. Bisulfite purification of these types of compounds was performed through isolation of a solid bisulfite adduct intermediate from aqueous alcoholic solution by filtration. Regeneration of an aldehyde or ketone from an isolated bisulfite adduct is accomplished using a base or a strong acid. Examples appearing in the literature of regeneration using bases includes: Na2CO3 in Org. Synthesis Coll. Vol. 4, 903 (1963); NaOH in WO 2006/074270 A2; and K2CO3 in Tetrahedron Lett., 45, 3219 (2004). Examples of regeneration using acids include: H2SO4 in J. Am. Chem. Soc., 70, 1748 (1948); and HCl in WO 99/57123.
For the preparation of a purified product, isolation of an intermediate solid bisulfite adduct is not preferred since filtration of the adduct is required. In addition, base regeneration of the adduct to yield the substrate is not appropriate in those cases wherein the regenerated product is unstable in basic conditions, for example, where the regenerated product is the compound of Formula I. When acid conditions are used to regenerate the substrate compound from a bisulfite adduct, generally strongly acidic conditions and heating are necessary (see references above).
Published international application no. WO 99/57123 reports using non-alcoholic solvent in a process for forming a bisulfite adduct, however the process required isolation of a solid bisulfite adduct and regeneration the substrate from the adduct using NaOH.
A non-aqueous method for regeneration of a substrate from the corresponding bisulfite adduct was reported in J. Org. Chem., 64, 5722 (1999) as a means to overcome side-reactions such as degradation and hydrolysis during regeneration of aldehyde/ketone with a base or an acid. In this method, trimethylsilyl chloride (TMSCl) or its equivalent was employed in acetonitrile. During the process TMS2O, NaCl, SO2 and HCl were generated as co-products when TMSCl was used. Removal of the co-products required the process steps of filtration (for NaCl), aqueous work-up (for NaCl and excess TMSCl) and distillation (for TMS2O), which requires use of a high boiling solvent. Regeneration of aldehydes from the corresponding bisulfite adducts with ammonium acetate in solvent-free conditions was reported in J. of Chem. Research, 237 (2004), however this process requires microwave irradiation. Published international application no. WO 2006/076415 describes regeneration of an aldehyde from a corresponding bisulfite adduct isolated from an alcoholic solvent system using a carbonate base with a lower alkyl carbonyl compound, for example, acetone and glyoxylic acid.